Mouse epidermal cell cultures and epidermal cell lines are utilized as models for studying mechanisms of epithelial carcinogenesis in vitro. Epidermal cells differentiate to produce keratin proteins and cornified envelopes. Low extracellular Ca ion concentration inhibits terminal differentiation and enhances proliferation while elevated Ca ion levels have the reverse effect. This may be mediated through Ca ion activation of epidermal transglutaminase. Tumor promoters also inhibit epidermal differentiation and activate ornithine decarboxylase. Retinoids inhibit tumor promoter induced ornithine decarboxylase prior to activation of enzyme transcription. Retinoids also inhibit promoter induced anchorage independence in epidermal cell lines. Corticosteroids, potent inhibitors of tumor promotion, effect promoter induced ornithine decarboxylase at a site subsequent to transcription and do not affect the conversion of epidermal cell lines to anchorage independence. Binding of the carcinogens acetylaminofluorene and benzo(a)pyrene to DNA of epidermal cells can be quantitated by a sensitive (less than 1 picomole) and specific radioimmunoassay. This assay can also detect quantitative or qualitative alterations in binding patterns found in different cell types or under differing exposure conditions.